Acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are a leading cause of morbidity and mortality in critically ill patients. Despite decades of research, there is still no effective therapy for ALI/ARDS, and treatment options are largely limited to supportive care. Neutrophil-mediated inflammation and endothelial cell (EC) injury are unifying features of the pathogenesis of ALI/ARDS. Interventions that suppress the contribution of neutrophils to the injury response and promote pulmonary vascular EC regeneration have been proposed as therapeutic strategies for ALI. However, neutrophil- suppressing therapies that were effective in animal models of ALI have yielded disappointing results in clinical trials in ALI/ARDS patients. Cell-based therapies, including mesenchymal stem cells and endothelial progenitor cells have emerged as potential treatment for ALI/ARDS, but most are currently at the preclinical level. Targeting delivery of cell to damaged organs has been recognized as one of the major hurdles for these cell therapies to be successfully translated into human patients. We have recently developed a highly innovative approach for the treatment of lipopolysaccharide (LPS)-induced ALI by intravenous transfusing pulmonary arterial (PA) ECs equipped with homing devices [interleukin (IL)-8 receptors RA/RB, CC chemokine receptors CCR2/5] to direct them to sites of inflammation/injury. In the current proposal, we will extend this targeted cell delivery strategy to a more applicable stem cell type, induced pluripotent stem cells (iPS)-derived ECs (iPS-ECs) to avoid possible cell rejection in future translational and/or clinical studies and to enhance the efficacy of tissue repair. We will further test this strategy using sepsis-related ALI models that more closely reflect the pathogenesis of ALI seen in clinical sepsis. We hypothesize that overexpressed IL8RA/RB and/or CCR2/5 will serve as a global positioning system for infused PAECs or iPS-ECs, homing them to injured lung and allowing them to compete with neutrophils for penetration into injured lung tissues, thus reducing inflammation and promoting healing. The Aims of this proposal are: 1) To test the hypothesis that targeted delivery of rat iPS-ECs overexpressing IL8RA/RB or CCR2/5 ameliorates inflammation and alveolar barrier disruption in LPS-injured lung. 2) To characterize the mechanisms by which targeted delivery of iPS-ECs overexpressing IL8RA/RB or CCR2/5 alleviates LPS-induced ALI. 3) To test the hypothesis that targeted delivery of iPS-ECs overexpressing IL8RA/RB or CCR2/5 ameliorates the injury response and promotes structural and functional recovery of cecal ligation-puncture (CLP)-injured rat lung. The results of the proposed studies will provide an innovative strategy for therapeutic interventions for patients with currently untreatable forms of ALI, such as ARDS.